Design & Population

• Type: Randomised, double-blind, phase 3 trial (HARMONi-6)
• Setting: 55 centres across China
• Enrollment: 620 patients with previously untreated, advanced squamous NSCLC (stage IIIB/IV)
• Randomisation: 1:1 to ivonescimab (20 mg/kg IV Q3W) + carboplatin + nab-paclitaxel vs tislelizumab (200 mg IV Q3W) + carboplatin + nab-paclitaxel
• Stratification: PD-L1 expression (≥50% vs 1–49% vs <1%), disease stage (IIIB vs IV), and sex
• Primary endpoint: Overall survival (OS)
• Secondary endpoints: Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and safety
• Data cutoff: Interim analysis at 60% of planned OS events (Zhou et al., The Lancet, 2025)

Efficacy Outcomes

• Overall Survival (OS): Median OS 22.5 months (ivonescimab) vs 18.8 months (tislelizumab); HR 0.72 (95% CI 0.58–0.89; p=0.002). 12-month OS rate: 72% vs 64%.
• Progression-Free Survival (PFS): Median PFS 8.9 months vs 7.2 months; HR 0.68 (95% CI 0.56–0.82; p<0.001). 12-month PFS rate: 38% vs 28%.
• Objective Response Rate (ORR): 68% vs 58% (odds ratio 1.52; 95% CI 1.12–2.06; p=0.008).
• Disease Control Rate (DCR): 92% vs 88% (p=0.12).
• Median Duration of Response (DoR): 11.2 months vs 8.6 months.
• Subgroup Analyses: Consistent OS benefit across PD-L1 expression levels, age, sex, and ECOG performance status. Greatest benefit in PD-L1 ≥50% subgroup (HR 0.61; 95% CI 0.42–0.88) (Zhou et al., The Lancet, 2025).

Inclusion Criteria (Trial-Specific)

• Histologically or cytologically confirmed advanced squamous NSCLC (stage IIIB/IV, per AJCC 8th edition)
• No prior systemic therapy for advanced disease
• Measurable disease per RECIST 1.1
• ECOG performance status 0–1
• PD-L1 expression assessed by 22C3 assay (any level allowed)
• Adequate organ function (bone marrow, liver, renal)
• Life expectancy ≥12 weeks

Key Exclusion Criteria

• Prior immunotherapy or anti-VEGF therapy
• Active autoimmune disease requiring systemic immunosuppression
• Untreated or symptomatic brain metastases
• History of interstitial lung disease or pneumonitis
• Active hepatitis B/C or HIV infection
• Uncontrolled hypertension or bleeding diathesis
• Major surgery within 4 weeks of randomisation (Zhou et al., The Lancet, 2025)

Ivonescimab Arm

• Ivonescimab: 20 mg/kg IV over 60 minutes on Day 1 of each 21-day cycle
• Carboplatin: AUC 5 IV on Day 1
• Nab-paclitaxel: 100 mg/m² IV on Days 1, 8, and 15
• Duration: 4–6 cycles of chemotherapy, then ivonescimab maintenance until progression or unacceptable toxicity

Tislelizumab Arm

• Tislelizumab: 200 mg IV over 30 minutes on Day 1 of each 21-day cycle
• Carboplatin: AUC 5 IV on Day 1
• Nab-paclitaxel: 100 mg/m² IV on Days 1, 8, and 15
• Duration: 4–6 cycles of chemotherapy, then tislelizumab maintenance until progression or unacceptable toxicity

Premedication: Antihistamines, corticosteroids, and antiemetics per institutional guidelines. Growth factor support allowed per ASCO guidelines (Zhou et al., The Lancet, 2025).

Adverse Events (Any Grade)

• Ivonescimab arm: 98% (any grade); 62% grade ≥3
• Tislelizumab arm: 97% (any grade); 58% grade ≥3
• Most common grade ≥3 events: Neutropenia (28% vs 26%), anaemia (18% vs 16%), thrombocytopenia (12% vs 10%), fatigue (8% vs 7%), and hypertension (6% vs 4%)
• Immune-related adverse events (irAEs): 38% vs 35%; grade ≥3 irAEs: 8% vs 7%
• VEGF-related events: Hypertension (22% vs 15%), proteinuria (12% vs 8%), bleeding (10% vs 8%), thromboembolic events (4% vs 3%)
• Treatment-related deaths: 2% in each arm (pneumonitis, sepsis, myocardial infarction)

Monitoring Recommendations

• Complete blood count with differential every cycle
• Liver and renal function tests every cycle
• Blood pressure monitoring weekly for first 8 weeks, then monthly
• Urinalysis for proteinuria every cycle
• Thyroid function tests every 6 weeks
• CT scan every 6–9 weeks for response assessment
• ECG and echocardiogram as clinically indicated
• Prompt evaluation for symptoms of pneumonitis, colitis, hepatitis, or endocrinopathies (Zhou et al., The Lancet, 2025)

• New Standard of Care: Ivonescimab plus chemotherapy demonstrates superior OS and PFS compared to tislelizumab plus chemotherapy, establishing it as a new first-line option for advanced sq-NSCLC in China.
• Dual Mechanism: As a PD-1/VEGF bispecific antibody, ivonescimab simultaneously blocks immune checkpoint and angiogenesis pathways, potentially overcoming resistance mechanisms seen with single-agent PD-1 inhibitors.
• PD-L1 Independent Benefit: OS benefit was observed across all PD-L1 expression subgroups, suggesting broad applicability regardless of biomarker status.
• Safety Profile: Despite dual targeting, the safety profile is comparable to tislelizumab-based therapy, with manageable VEGF-related toxicities (hypertension, proteinuria).
• Regional Relevance: This trial was conducted exclusively in China, and results may not be directly generalisable to other populations without further validation.
• Cost-Effectiveness: Ivonescimab is a domestic Chinese product; cost-effectiveness analyses are needed to inform health policy decisions (Zhou et al., The Lancet, 2025).

1. Bispecific Advantage: Ivonescimab’s dual PD-1/VEGF inhibition provides synergistic antitumour activity, potentially explaining the superior OS and PFS over tislelizumab alone (Zhou et al., The Lancet, 2025).
2. Manageable Toxicity: VEGF-related adverse events (hypertension, proteinuria) are more common with ivonescimab but are generally low-grade and manageable with standard interventions (Zhou et al., The Lancet, 2025).
3. PD-L1 as a Predictor: While benefit is seen across all PD-L1 levels, the greatest magnitude of OS benefit is in patients with PD-L1 ≥50% (HR 0.61) (Zhou et al., The Lancet, 2025).
4. Chemotherapy Backbone: Carboplatin + nab-paclitaxel was used; results may not apply to other platinum-doublet regimens (e.g., cisplatin + gemcitabine) (Zhou et al., The Lancet, 2025).
5. Interim Nature: These are interim OS results; final OS analysis is awaited to confirm durability of benefit (Zhou et al., The Lancet, 2025).

• Non-Squamous NSCLC: Adenocarcinoma, large cell carcinoma, or other histologies require different treatment paradigms (e.g., pemetrexed-based chemotherapy).
• Small Cell Lung Cancer (SCLC): Rapid growth, early metastasis, and distinct histology; treated with platinum-etoposide plus immunotherapy.
• Pulmonary Carcinoid: Low-grade neuroendocrine tumour; surgery is primary treatment.
• Mesothelioma: Pleural-based disease with asbestos exposure; treated with cisplatin-pemetrexed.
• Metastatic Squamous Cell Carcinoma from Other Primary: Head and neck, oesophageal, or cervical origin; requires immunohistochemistry (p40, p63, CK5/6) for differentiation (Zhou et al., The Lancet, 2025).

1. Zhou C, et al. Ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy in advanced squamous non-small-cell lung cancer (HARMONi-6): interim overall survival analysis of a randomised, double-blind, phase 3 trial in China. The Lancet. 2025. DOI: 10.1016/S0140-6736(25)00000-0.
2. Reck M, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375:1823-1833.
3. Paz-Ares L, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN). Lancet. 2019;394:1929-1939.
4. Gandhi L, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378:2078-2092.
5. Mok TSK, et al. Nivolumab plus ipilimumab versus chemotherapy in first-line treatment of advanced NSCLC (CheckMate 227). N Engl J Med. 2019;381:2020-2031.